Transcriptional Mechanisms of Vascular Inflammation Dr. Mark W. Feinberg's research interests involve the identification of transcription factors governing cellular differentiation and activation focusing on cell types that participate in the development of vascular disease states (monocytes/macrophages, T cells, smooth muscle cells, endothelial cells). There are two major areas of investigation - one focusing on a transcription factor family termed Kruppel-like Factors (KLFs) and a second on transforming growth factor (TGF)-b1 and Smad signaling in macrophages and T cells. Through the elaboration of pro-inflammatory cytokines and growth factors, macrophages and CD4+ T cells are critical to the development of a variety of inflammatory disease states, including arteriosclerosis and transplant arteriopathy. Current research efforts seek to identify transcriptional regulators that may alter these processes. Dr. Feinberg's laboratory has identified one member of the KLF family as a critical regulator of monocyte commitment, differentiation, and macrophage activation. Another KLF identified plays an important role in T regulatory (CD4+CD25+) cell function, an important cell type implicated in suppressing vascular inflammation. Dr. Feinberg's studies demonstrate that macrophage activation can be uniquely inhibited through a TGF-b1 superfamily protein, Smad3. Using gain- and loss-of-function strategies, current research is aimed to elucidate molecular mechanisms of Smad3 and other TGF-b regulated genes involved in limiting macrophage and T cell activation. These studies may allow for novel therapeutic strategies for treatment of inflammatory states such as atherosclerosis.
References:
Feinberg M.W., Wara AK, Cao Z, Lebedeva MA, Rosenbauer F, Iwasaki H, Hirai H, Katz JP, Haspel RL, Gray S, Akashi K, Segre J, Kaestner KH, Tenen DG, Jain MK. The Kruppel-like factor KLF4 is a critical regulator of monocyte differentiation. EMBO J. 2007 Sep 19;26(18):4138-48.
Feinberg, M.W., Cao Z., Wara AKM., Lebedeva, M.A., Senbanerjee, S., Jain, M.K. Kruppel-like factor 4 (KLF4) is a mediator of proinflammatory signaling in macrophages. Journal of Biological Chemistry, 2005;280(46):38247-58.
Feinberg, M.W., Li, Z., Fisch, S., Jain, M.K. Kruppel-like factors in the vascular system. Trends in Cardiovascular Medicine 2004;14:241-6.
Feinberg, M.W., Shimizu, K., Lebedeva, M., Haspel, R., Takayama, K., Chen, Z., Frederick, J.P., Wang, X.F., Simon, D.I., Libby, P., Mitchell, R.N., Jain, M.K. Essential role for Smad3 in regulating MCP-1 expression and vascular inflammation. Circulation Research 2004;94:601-8.
Feinberg, M.W., Watanabe, M., Lebedeva, M.A., Depina, A.S., Hanai, J., Mammoto, T., Frederick, J.P., Wang, X.F., Sukhatme, V.P., Jain, M.K. Transforming growth factor-beta 1 inhibition of vascular smooth muscle cell activation is mediated via Smad3. Journal of Biological Chemistry 2004;279:16388-93.
Feinberg, M.W., Jain, M.K., Werner, F., Sibinga, N.E., Wiesel, P., Wang, H., Topper, J.N., Perrella, M.A., Lee, M.E. Transforming growth factor-beta 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. Journal of Biological Chemistry 2000;275:25766-73.
Feinberg, M.W. and Jain M.K. Role of TGF-b1/Smads in regulating vascular inflammation and atherogenesis. PanMinerva Medica. 2005;47(3):169-86.
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